Neurofibrillary pathology in AD and other neurodegenerative diseases results from the aggregation and deposition of normal tau proteins. However, transgenic mouse models overexpressing a wild-type human tau transgene rarely develop neuropathology. Failure of tau to aggregate in these models may be due to small structural differences between mouse and human tau amino acid sequences. Development of age- related neuropathology, similar to that observed in AD, in a mouse model overexpressing the entire human tau transgene on a knockout mouse tau background (htau mice) provides support for this idea. Therefore, we hypothesize that mouse tau inhibits the aggregation of human tau, and thus, overexpression of mouse tau alone should be sufficient to drive the development of neurofibrillary pathology. To test this hypothesis, we plan to use both in vitro and in vivo methods to examine mouse tau aggregation and its effects on human tau aggregation. The specific aims are: (1) To determine the assembly and aggregation behavior of different human tau proteins alone and in the presence of mouse tau using cell-free assay systems;(2) To characterize a transgenic mouse model overexpressing normal mouse tau (mtau mice) regarding various aspects of tau biology as well as any accompanying pathological changes;and (3) To model mouse and human tau interactions in vivo through cross-breeding studies of the mtau mice with a single human tau isoform expressing mouse model (WT 4R) or a genomic human tau expressing mouse model (8c mice). The widespread use of transgenic mouse models for the study of AD and other neurodegenerative diseases underlines the importance of understanding the assembly behavior of different human tau isoforms in the presence of mouse tau. Additionally, characterization of this mouse model should provide a simple yet realistic model of how tau pathogenesis causes neurodegeneration. Mouse models developed to study Alzheimer's disease (AD), the leading cause of dementia in the elderly, have failed to reproduce a key feature of the disease, robust NFT pathology containing normal tau proteins. Since these models over-express a normal human tau gene, as well as, the normal mouse tau gene, it is possible that small differences between these two species'proteins may interfere with their ability to aggregate, thereby preventing the development of pathology. The purpose of this study is to determine whether human and mouse tau proteins are co-inhibitory, and to develop a simple model of normal tau aggregation to study this important component of AD.